10,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylisocyanate compounds

ABSTRACT

Tetrafluoro derivatives of 10,11-dihydrodibenzo[a,d]cyclohepten-5-aminomethyl compounds and the corresponding N-substituted derivatives thereof, useful as antiarrhythmic agents, are prepared from tetrafluoro derivatives of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one by reduction to the corresponding 5-ol compound and subsequently converting said 5-ol compound to the corresponding 5-halo and the 5-aminomethyl derivatives by reactions known in the prior art.

This is a division of copending U.S. application Ser. No. 569,134, filedApr. 17, 1975, now U.S. Pat. No. 4,020,096, which in turn is a divisionof U.S. application Ser. No. 438,924, filed Feb. 1, 1974, which issuedApr. 13, 1976 as U.S. Pat. No. 3,950,423.

This invention relates to tetrafluoro derivatives of10,11-dihydro-dibenzo[a,d]cyclohepten-5-aminomethyl compounds and thecorresponding N-substituted derivatives, such as the N-alkyl andN,N-dialkyl derivatives thereof. More specifically, it relates tosubstituted and unsubstituted derivatives of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamineand to the N-alkyl, e.g., N-methyl or N-ethyl, and the N,N-dialkyl,e.g., N,N-dimethyl or N,N-diethyl derivatives thereof.

This invention also relates to the novel processes and the novelintermediates utilized in the production of the new10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamines, topharmaceutical formulations of the new tetrafluorodibenzocycloheptenemethylamines, and to methods of treating or preventing cardiacarrhythmias using the novel compounds and/or pharmaceutical formulationsthereof described hereinafter.

The new compounds of this invention are10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylaminesand the corresponding N-substituted and N-alkyl or N,N-dialkylderivatives thereof represented by the following formula: ##STR1##wherein R₂ and R₃ can be alike or different and are either hydrogen,alkyl, aralkyl, alkenyl, alkynyl, or can be joined together through anatom of nitrogen, oxygen, or sulfur to form a heterocyclic ring of from5-6 atoms, or a derivative of one of the abovetetrafluorodibenzocycloheptene-methylamine compounds in which one ormore of the hydrogen atoms attached to the 1-, 2-, 3-, 4-, 6-, 7-, 8- or9- positions is replaced by halogen, alkyl, alkoxy, perfluoroalkyl,alkylmercapto, alkylsulfonyl, and dialkylsulfamoyl.

A preferred class of compounds of the present invention may berepresented structurally in accordance with the above formula in whichthe R₂ and R₃ substituents are preferably loweralkyl substituents offrom 1-6 carbon atoms or hydrogen, and the ring substituent at the 1-,2-, 3-, 4-, 6-, 7-, 8- or 9- position is either hydrogen, halogenselected from chlorine or fluorine, loweralkyl of from 1-6 carbon atoms,loweralkoxy of from 1-5 carbon atoms, trifluoromethyl, loweralkylmercapto of from 1-6 carbon atoms, loweralkyl sulfonyl of from 1-6carbon atoms, and dialkylsulfamoyl of from 2-8 carbon atoms.

An especially preferred group of compounds included within the scope ofthe present invention is represented by the formula ##STR2## in whichthe R₂ and R₃ substituents are either hydrogen, loweralkyl of from 1-6carbon atoms or any combination thereof. Illustrative of the compoundsincluded within the scope of the present invention are10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,the N-methyl derivative of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,and the N,N-dimethyl derivative of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine.

Also included among the compounds useful in the method of the presentinvention are the N-oxides of the tertiary amines and the non-toxicpharmaceutically acceptable salts of the amines and N-oxides, thepreferred salts being the non-toxic acid addition salts such as thehydrochloride, the maleate, and the like.

The compounds represented above, in either their free base or salt form,possess useful pharmacological properties. In particular, they have beenfound to possess antiarrhythmic activity. It has been found that theadministration of compounds of the present invention, depicted in theabove formula, results in the prevention of arrhythmia in animals underconditions which ordinarily cause the development of arrhythmia in theanimal 100 percent of the time.

It has further been found that administration of the compounds of thepresent invention will arrest an existing arrhythmia in the animal beingtreated and cause a resumption of normal cardiac rhythm. Asantiarrhythmic agents, these compounds may be administered orally orparenterally. The formulations for administration may be prepared inconventional manner, employing conventional pharmaceutical carriers andexcipients.

The non-toxic acid addition salts useful as components in thecompositions provided by the present invention are salts formed by thereaction of an equivalent amount of the amine compound of the aboveformula and an acid which is pharmacologically acceptable in theintended doses. Salts of the above compound which are useful are saltsof the amine with hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, fumaric acid, acetic acid, propionic acid, lactic acid,gluconic acid, maleic acid, succinic acid, tartaric acid, and the like.Salts of these acids with the amine base are useful as the activecomponent of the compositions in the method of this invention.

The daily doses are based on the total body weight of the test animaland vary between about 1.00 and 100.00 mg./kg. for mature animals. Thus,a unit dose based on four-times-a-day administration is between 2.5 mg.and 250 mg. for a 10 kg. dog, and a total daily dose for a 10 kg. dogwould vary between about 10 mg. and 1000 mg. For larger animals, up to100 kg. and above, proportional dosages are employed, based on theweight of the animal. Suitable dosage units provided for theadministration of of the compositions used in the method of theinvention are tablets, capsules (which may be suitably formulated foreither immediate or sustained release), syrups, elixirs, parenteralsolutions, and the like. These dosage forms preferably contain per unitone or more multiples of the desired dosage unit in combination with thepharmaceutically acceptable diluent or carrier required for preparingthe dosage unit.

The condition of arrhythmia is a change in the normal rhythm of theheart which is noted in the higher forms of life, particularly thelarger mammals including dogs, horses, cattle and man. This disturbancein the normal rhythm of the heart of the affected animal may arisespontaneously without apparent cause or it may result from a seriousheart condition. Depending on the type of arrhythmia present in theaffected patient, it may vary from a momentary effect which willspontaneously be corrected, or in extremely acute cases may result inalmost instantaneous death. It is therefore desirable to provide amethod of treatment for acute episodes of arrhythmia in the affectedpatient or, alternatively, to provide a method of prophylaxis includingthe administration of an agent useful in preventing arrhythmias topatients prone to such disturbances of normal heart rhythm.

One of the principal methods of treating arrhythmia using drug therapyin the past has been the administration of quinidine or procaine amide.This method suffers from toxic side effects associated with the drugswhich often occur concurrently with the administration of the drug.Particularly important are gastrointestinal disturbances caused by thedrugs as well as the possibility of vascular collapse. One difficultywith the administration of these prior art drugs is that the toxic sideeffects occurs at a dosage level recommended for effective control ofthe arrhythmia.

In addition to quinidine and procaine amide, which have been the drugsof choice for treating arrhythmia in the past, other compounds moreclosely related in structure to the compounds of the present inventionhave been reported to be active as antiarrhythmic agents. Thus, U.S.Pat. No. 3,527,871 of Engelhardt and Torchiana reports that certaindibenzocycloheptene-5-methylamines are active as antiarrhythmic agents.However, it has been noted in the past that certain pharmacologicallyactive dibenzocycloheptene compounds are metabolized through oxidationof the cycloheptene ring structure at the 10 or 11 carbons, i.e., theethane or ethylene bridge between the two rings. In accordance with thepresent invention, there is produced a class of10,10,11,11-tetrafluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptenes whichhave a perfluorinated ethane substituent bridging the benzene rings.This perfluoro ethane bridge is resistant to known chemical means ofoxidation. The class of compounds however has been found to be active asantiarrhythmic agents, as shown by the ability of the compounds toarrest an existing arrhythmia or prevent the development of arrhythmiain animals under conditions which ordinarily cause such disturbances ofthe heart rhythm.

It has now been found in accordance with the present invention thatadministration of the compounds of the present invention depicted in theabove formula results in the prevention of arrhythmia in animals underconditions which ordinarily cause the development of arrhythmia in theanimal 100 percent of the time. It has further been found thatadministration of the compounds of the present invention will arrest anexisting arrhythmia in the animal being treated and cause a resumptionof normal cardiac rhythm.

The compounds represented by the above structural formulae may beprepared as illustrated below: ##STR3## in which R₁ is a loweralkylsubstituent and X is halogen. As indicated hereinabove, the aromaticrings of the above compounds are substituted optionally by replacementby one or more of the hydrogen atoms attached to the 1-, 2-, 3-, 4-, 6-,7-, 8-, or 9- positions by halogen, especially chlorine or bromine,alkyl, preferably of from 1-6 carbon atoms, alkoxy, preferablyloweralkoxy of from 1-5 carbon atoms, perfluoroalkyl, especiallytrifluoromethyl or pentafluoroethyl, alkylmercapto, preferablycontaining from 1-6 carbon atoms, alkylsulfonyl, preferably of from 1-6carbon atoms, and dialkylsulfamoyl, preferably having from 2-8 carbonatoms.

In carrying out the process of the present invention, Compound Ihereinabove,10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one,or a derivative thereof, is contacted with a reducing agent selectedfrom alkali or alkaline earth metal borohydrides, dissolved in a solventrelatively inert under reaction conditions comprising either aloweralkanol such as ethyl alcohol or isopropyl alcohol or an ether,such as dioxane or tetrahydrofuran, at a temperature of from 0° C. tothe reflux temperature of the solvent for a period of from 1-6 hours toproduce a corresponding10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-olwhich, in turn, is treated with a halide compound selected from hydrogenchloride or hydrogen bromide, a phosphorous halide such as phosphorouspentachloride, or thionyl chloride. In carrying out the steps of thereaction, the cyclohepten-5-ol compound is treated with stirring at atemperature between about 0°-50° C. with thionyl chloride in at leastequimolar amounts to produce the corresponding5-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene.The chloro substituent of the dibenzocycloheptene compound is thenreplaced with a malonic ester substituent by contacting the 5-halocompound with a loweralkyl ester of malonic acid in the presence of astrong base such as sodium hydride at a temperature of from 0° C. to100° C. Preferably the malonate ester is first mixed with sodium hydridein mineral oil and the solution of malonic ester is then treated with anappropriate amount of the5-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepteneto produce the desired10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]-cycloheptene-5-malonatedialkyl ester. The malonate ester is then decarboxylated by heating witha solution of a strong base, advantageously an alcoholic solution of analkali metal hydroxide, to produce a corresponding10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]-cycloheptene-5-aceticacid.

The acetic acid derivative is then rearranged utilizing known reactionconditions by first forming the corresponding acid azide, rearrangingthe azide to the isocyanate by heating, and treating a solution of theisocyanate with methanol to produce the N-methoxy carbonyl derivative of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine.The N-methoxycarbonyl derivative thus formed is hydrolyzed to producethe corresponding primary amine,10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine.The cycloheptene-5-methylamine compound is then converted by treatmentwith formaldehyde and formic acid in accordance with the knownEschweiler-Clarke modification of the Leuckart Reaction to produce thecorresponding N,N-dimethyl derivative of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine.

In an alternative step of the process, the formed N-alkoxycarbonylderivative of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamineis reduced with an alkali metal aluminum hydride to produce thecorresponding secondary amine, i.e., the N-methyl derivative of thepreceding compound.

The starting material utilized in the process of the present inventionis readily prepared from the known10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10,11-dione by reaction withsulfur tetrafluoride in the presence of hydrogen fluoride at atemperature of from 100°-160° C. for a period of several hours. Incarrying out this conversion, it is preferable to first mix thereactants, i.e., the dione compound, along with the sulfur tetrafluorideand a small amount of hydrogen fluoride as a catalyst, and agitate forfirst 2 hours at 120° C. followed by elevation of the temperature for anadditional 2 hours at 140° C., followed by elevation of the temperaturefor an additional 6 hours at 160° C. When the dione is treated in thismanner, the desired10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-oneis obtained. The tetrafluoroketone prepared in this manner is thenpurified using a combination of techniques involving sublimation, columnchromatography, and recrystallization. In order to prepare derivativesof the 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10,11-dione in whichone of the hydrogens at the 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- positionsis replaced by a substituent selected from halogen, alkyl, alkoxy,perfluoroalkyl, alkylmercapto, alkylsulfonyl, and dialkylsulfamoyl, itis preferred to employ an appropriately substituted o-benzyl benzoicacid. Available o-benzyl benzoic acids having the desired substitutionin the aromatic rings are employed or known techniques for introducingthe desired substituent in the desired position of the aromatic ring areemployed. The benzyl benzoic acid is subjected to a homologationprocedure involving reduction of the acid to the corresponding benzylalcohol with lithium aluminum hydride, conversion of the benzyl alcoholto the corresponding benzyl bromide using hydrogen bromide, reaction ofthe benzyl bromide with an alkali metal cyanide to produce thecorresponding o-benzyl phenylacetonitrile, followed by hydrolysis of thenitrile under acidic conditions to produce the corresponding o-benzylphenylacetic acid compound. This phenyl acetic acid compound is thentreated in a Friedel-Crafts type reaction using anhydrous aluminumchloride to produce the10,11-dihydro-10-oxo-5H-dibenzo[a,d]cycloheptene, which in turn isoxidized using a mild oxidizing agent such as selenous acid, to producethe starting material utilized in the process of the present invention,i.e., the 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-10,11-dione or aderivative thereof in which the ring substituent at the 1-, 2-, 3-, 4-,6-, 7-, 8- or 9- positions is either hydrogen, halogen selected fromchlorine or fluorine, loweralkyl of from 1-6 carbon atoms, loweralkoxyof from 1-5 carbon atoms, trifluoromethyl, loweralkyl mercapto of from1-6 carbon atoms, loweralkyl sulfonyl of from 1-6 carbon atoms, anddialkylsulfamoyl of from 2-8 carbon atoms. This method of preparing thestarting material is outlined structurally below: ##STR4##

PREPARATION OF STARTING MATERIALS Preparation 1

10,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]-cyclohepten-5-one

10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-10,11-dione, 0.8 g. (0.0036mole), together with 75 g. of sulfur tetrafluoride, 1 g. of mercury anda trace of hydrogen fluoride, is charged into a stainless steelautoclave and shaken 2 hours at 120° C., 2 hours at 140° C. and 6 hoursat 160° C. After cooling and venting the vessel, the mixture isdissolved in chloroform, separated from mercury, and filtered throughdiatomaceous earth. Evaporation of solvent from the filtrate under thereduced pressure leaves an oily black solid as the residue that istriturated with 75 ml. of boiling hexane. The hexane-insoluble materialis removed by filtration and evaporation of solvent from the filtrateunder reduced pressure leaves the crude product as an oily black solid.Sublimation at 70°-75° C. and 0.05 mm. yields slightly oily, pale yellowcrystals, m.p. 69°-77° C. to a cloudy melt clear at 110° C. Purificationis effected by column chromatography on 50 g. of silica gel, the productbeing eluted with carbon tetrachloride. The fractions that show one spotof Rf 0.2 on a silica thin layer plate developed with carbontetrachloride are combined. Evaporation of the solvent under reducedpressure leaves white crystals, m.p. 73°-76° C. A sample for analysis issublimed at 65° C. and 0.05 mm. and recrystallized twice from isopropylalcohol-water; m.p. 75.5°-77.5° C.

Anal. Calc'd. for C₁₅ H₈ F₄ O: C, 64.28; H, 2.88; F, 27.12. Found: C,64.04; H, 2.88; F, 27.04.

The procedure of the preceding paragraph is repeated utilizing as thestarting material the appropriate amount of the substituted10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-10,11-dione to produce thecorrespondingly substituted10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one,as follows:

    ______________________________________                                        STARTING MATERIAL                                                                              PRODUCT                                                      ______________________________________                                        10,11-dihydro-1-fluoro-5H-                                                                     10,11-dihydro-1,10,10,11,11-                                 dibenzo[a,d]cyclohepten-                                                                       pentafluoro-5H-dibenzo[a,d]-                                 10,11-dione      cyclohepten-5-one                                            3-chloro-10,11-dihydro-5H-                                                                     3-chloro-10,11-dihydro-                                      dibenzo[a,d]cyclohepten-                                                                       10,10,11,11-tetrafluoro-5H-                                  10,11-dione      dibenzo[a,d]cyclohepten-5-one                                10,11-dihydro-3-methyl-5H-                                                                     10,11-dihydro-3-methyl-10,10,-                               dibenzo[a,d]cyclohepten-                                                                       11,11-tetrafluoro-5H-dibenzo-                                10,11-dione      [a,d]cyclohepten-5-one                                       3,7-dimethyl-10,11-dihydro-                                                                    3,7-dimethyl-10,11-dihydro-                                  5H-dibenzo[a,d]cyclohepten-                                                                    10,10,11,11-tetrafluoro-5H-                                  10,11-dione      dibenzo[a,d]cyclohepten-5-one                                10,11-dihydro-4-methoxy-5H-                                                                    10,11-dihydro-4-methoxy-                                     dibenzo[a,d]cyclohepten-10,11-                                                                 10,10,11,11-tetrafluoro-5H-                                  dione            dibenzo[a,d]cyclohepten-5-one                                10,11-dihydro-3-ethoxy-5H-                                                                     10,11-dihydro-3-ethoxy-                                      dibenzo[a,d]cyclohepten-                                                                       10,10,11,11-tetrafluoro-5H-                                  10,11-dione      dibenzo[a,d]cyclohepten-5-one                                3,7-diethoxy-10,11-dihydro-                                                                    3,7-diethoxy-10,11,-dihydro-                                 5H-dibenzo[a,d]cyclohepten-                                                                    10,10,11,11-tetrafluoro-5H-                                  10,11-dione      dibenzo[a,d]cyclohepten-5-one                                10,11-dihydro-3-trifluoro-                                                                     10,11-dihydro-3-trifluoro-                                   methyl-5H-dibenzo[a,d]-                                                                        methyl-10,10,11,11-tetrafluoro-                              cyclohepten-10,11-dione                                                                        5H-dibenzo[a,d]cyclo-                                                         hepten-5-one                                                 10,11-dihydro-3-methyl-                                                                        10,11-dihydro-3-methyl-                                      mercapto-5H-dibenzo[a,d]                                                                       mercapto-10,10,11,11-tetrafluoro-                            cyclohepten-10,11-dione                                                                        5H-dibenzo[a,d]cyclo-                                                         hepten-5-one                                                 10,11-dihydro-4-propyl-                                                                        10,11-dihydro-4-propyl-                                      mercapto-5H-dibenzo[a,d]-                                                                      mercapto-10,10,11,11-tetrafluoro-                            cyclohepten-10,11-dione                                                                        5H-dibenzo[a,d]cyclo-                                                         hepten-5-one                                                 10,11-dihydro-3-ethyl-                                                                         10,11-dihydro-3-ethylsulfonyl-                               sulphonyl-5H-dibenzo[a,d]-                                                                     10,10,11,11-tetrafluoro-5H-                                  cyclohepten-10,11-dione                                                                        dibenzo[a,d]cyclohepten-5-one                                3-diethylsulfamoyl-10,11-                                                                      3-diethylsulfamoyl-10,11-                                    dihydro-5H-dibenzo[a,d]-                                                                       dihydro-10,10,11,11-tetrafluoro-                             cyclohepten-10,11-dione                                                                        5H-dibenzo[a,d]cyclo-                                                         hepten-5-one                                                 ______________________________________                                    

Preparation 2

10,11-Dihydro-5,5,10,10,11,11-hexafluoro-5H-dibenzo[a,d]-cycloheptene

10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-10,11-dione, 1.0 g. (0.0045mole), together with 48 g. of sulfur tetrafluoride, 1 g. of mercury anda trace of hydrogen fluoride, is charged into a stainless steelautoclave and shaken 10 hours at 80° C. After cooling and venting thevessel, the mixture is dissolved in chloroform, separated from mercury,and filtered. Evaporation of solvent from the filtrate under reducedpressure leaves an oily dark blue residue that is triturated with 150ml. of boiling hexane. The hexane-insoluble material is removed byfiltration and evaporation of solvent from the filtrate under reducedpressure leaves the crude product as the residue. Sublimation at 70° C.and 0.1 mm. yields oily off-white solid that is triturated with carbontetrachloride. The insoluble material is removed by filtration and thefiltrate is concentrated and applied to a chromatographic column of 70g. of silica gel. The product is eluted with carbon tetrachloride,collecting the fractions that show essentially one spot of Rf 0.7 on asilica thin layer plate developed with carbon tetrachloride. Evaporationof the solvent under reduced pressure and sublimation of the residue at55°-60° C. and 0.1 mm. yields white crystals, m.p. 53°-55° C. to aslightly cloudy melt.

Anal. Calc'd. for C₁₅ H₈ F₆ : C, 59.61; H, 2.67; F, 37.72. Found: C,59.54; H, 3.11; F, 35.80.

Preparation 3

10,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]-cyclohepten-5-one

A solution of 989 mg. (0.00328 mole) of10,11-dihydro-5,5,10,10,11,11-hexafluoro-5H-dibenzo[a,d]cycloheptene in13.2 ml. of glacial acetic acid - 3.5 ml. of 6 N hydrochloric acid isheld at room temperature for approximately 20 hours, heated in a 65° C.bath for 3 hours, again held at room temperature for about 20 hours, andfinally heated in a 65° C. bath for 3 hours. The solution isconcentrated under reduced pressure and the residue partitioned betweenbenzene and water. The benzene extract is washed with water, dried overanhydrous sodium sulfate, and evaporated to dryness under reducedpressure. Sublimation of the residue at 80° C. and 0.1 mm. yields thecrude product as an oily solid. Purification is effected by columnchromatography on silica gel, the product being eluted with carbontetrachloride. The fractions that show one spot of Rf 0.1 on a silicathin layer plate developed with carbon tetrachloride are combined.Evaporation of the solvent under reduced pressure leaves the whitecrystalline product, m.p. 76°-78° C.

Preparation 4

10,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene

10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-10,11-dione, 2.2 g. (0.01mole), together with 107 g. of sulfur tetrafluoride, 1 g. of mercury, atrace of hydrogen fluoride, and 25 ml. of methylene chloride, is chargedinto a stainless steel autoclave and shaken 10 hours at 80° C. Aftercooling and venting the vessel, the mixture is separated from mercuryand filtered. Evaporation of solvent from the filtrate under reducedpressure leaves a brown oil as the residue that is triturated with 150ml. of hexane. The insoluble tar is removed by filtration andevaporation of solvent from the filtrate under reduced pressure leavesthe crude product as an oil. Sublimation at 50°-55° C. and 0.05 mm.yields white crystals, m.p. 53.5°-55° C. A sample for analysis from aprevious preparation was purified by column chromatography on silicagel, eluting the product with carbon tetrachloride. Evaporation ofsolvent under reduced pressure and sublimation of the residual slid at60°-70° C. and 0.8 mm. gave purified product, m.p. 53.5°-56° C.

Anal. Calc'd. for C₁₅ H₁₀ F₄ : C, 67.67; H, 3.79; F, 28.55. Found: C,67.38; H, 3.89; F, 28.56.

Preparation 5

10,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d] cyclohepten-5-one

A mixture of 1.45 g. (0.00544 mole) of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene, 0.73g. (0.0073 mole) of chromium trioxide, 25 ml. of trifluoroacetic acidand 2 ml. of glacial acetic acid is stirred at reflux for 21/4 hours.During this period, almost all of the chromium trioxide dissolves.Solvents are evaporated under reduced pressure and the residue ispartitioned between benzene and water. The aqueous layer is separatedand re-extracted twice with benzene. The combined benzene extracts arewashed thoroughly with water, dried over anhydrous magnesium sulfate,and evaporated to dryness under reduced pressure. The crude product isleft as the residual oily solid and is purified by column chromatographyon 75 g. of silica gel, eluting the product with 1:1 benzene-carbontetrachloride. The fractions that show one spot of Rf 0.75 on a silicathin layer plate developed with benzene are combined. Evaporation of thesolvent under reduced pressure leaves the white crystalline product,m.p. 70°-75° C.

EXAMPLE 110,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

A solution of 190 mg. (0.005 mole) of sodium borohydride in 1 ml. ofwater is added dropwise to a stirred solution of 830 mg. (0.00296 mole)of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-onein 10 ml. of isopropyl alcohol. After stirring the mixture for 3 hoursat room temperature and 30 minutes at reflux, the isopropyl alcohol isevaporated under reduced pressure. The residue is partitioned betweenbenzene and water and the benzene extract is separated, washed, anddried. Evaporation under reduced pressure leaves the product as theresidual pale yellow oil. A sample for analysis is evaporativelydistilled at 80° C. and 0.1 mm.

Analysis calc'd. for C₁₅ H₁₀ F₄ : C, 63.84; H, 3.57; F, 26.94. Found: C,63.93; H, 3.34; F, 26.78.

The procedure of the preceding paragraph is repeated using as startingmaterial, instead of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one,the products obtained in accordance with the second paragraph ofPreparation 1 with resultant production of the following products:

10,11-dihydro-1,10,10,11,11-pentafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

3-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]-cyclohepten-5-ol

10,11-dihydro-3-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

3,7-diethyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

10,11-dihydro-4-methoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

10,11-dihydro-3-ethoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

3,7-diethoxy-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

10,11-dihydro-3-trifluoromethyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

10,11-dihydro-3-methylmercapto-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

10,11-dihydro-3-propylmercapto-10,10,11,11-tetrafluoro-5H-diabenzo[a,d]cyclohepten-5-ol

10,11-dihydro-3-ethylsulfonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

3-diethylsulfamoyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol

EXAMPLE 25-Chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene

A solution of 665 mg. (0.00236 mole) of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-ol in5 ml. of dry benzene is stirred, cooled to 10°-15° C. in an ice bath andtreated dropwise with 0.2 ml. of thionyl chloride. After allowing thelight yellow solution to come to room temperature, it is heated torefluxing for approximately 18 hours and the solution is evaporated todryness under reduced pressure. The residual solid is flushed withbenzene three times to remove the last traces of thionyl chloride andfinally dried under reduced pressure at 50° C. for 1 hour, yieldingproduct, m.p. 129°-132° C. Recrystallization from petrleum ether(30°-60° C.) affords a purified sample, m.p. 131.5°-133.5° C.

Anal. Calc'd. for C₁₅ H₉ ClF₄ : C, 59.91; H, 3.02; Cl, 11.80. Found: C,60.25; H, 3.26; Cl, 11.63.

The procedure of the preceding paragraph is repeated using as startingmaterial instead of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-olthe products obtained in accordance with the second paragraph of Example1 with resultant production of

5-chloro-10,11-dihydro-1,10,10,11,11-pentafluoro-5H-dibenzo[a,d]cycloheptene,

3,5-dichloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,

5-chloro-10,11-dihydro-3-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,

5-chloro-10,11-dihydro-3,7-dimethyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,

5-chloro-10,11-dihydro-4-methoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,

5-chloro-10,11-dihydro-3-ethoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,

5-chloro-3,7-diethoxy-10,11-dihydro-10,10,11,11,-tetrafluoro-5H-dibenzo[a,d]cycloheptene,

5-chloro-10,11-dihydro-3-trifluoromethyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,

5-chloro-10,11-dihydro-3-methylmercapto-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,

5-chloro-10,11-dihydro-4-propylmercapto-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,

5-chloro-10,11-dihydro-3-ethysulfonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,and

5-chloro-3-diethylsulfamoyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene.

EXAMPLE 3Diethyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate

Diethyl malonate, 90 ml., is stirred, cooled in an ice bath, and treatedwith 1.51 g. of 55.7% sodium hydride in mineral oil in several portions.The mixture is stirred approximately 5 minutes at room temperature andthen treated with 10.03 g. (0.0334 mole) of5-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene.Stirring is continued for 16 hours at approximately 40° C., 1 hour at50° C., 1 hour at 60° C. and 1 hour at 70° C. The excess diethylmalonate is distilled at 70°-75° C. and 0.1 mm. and the residue istriturated with hexane. The insoluble mixture of product and sodiumchloride is collected, washed with hexane and petroleum ether, and driedat 80° C. and 0.1 mm. The mixture is triturated with benzene and theinsoluble sodium chloride is removed by filtration. Evaporation of thebenzene solution under reduced pressure and recrystallization of theresidual white solid from absolute ethanol affords purified product,m.p. 144°-146° C.

Anal. Calc'd. for C₂₂ H₂₀ F₄ O₄ : C, 62.26; H, 4.75; F, 17.90. Found: C,62.59; H, 4.52; F, 17.46.

The procedure of the preceding paragraph is repeated using as startingmaterials, instead of5-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene,the products obtained in accordance with the second paragraph of Example2 with resultant production of

Diethyl-10,11-dihydro-1,10,10,11,11-pentafluoro-5H-dibenzo[a,d]cycloheptene-5malonate

Diethyl-3-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate

Diethyl-10,11-dihydro-3-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate

Diethyl-3,7-diethyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate

Diethyl-10,11-dihydro-4-methoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate

Diethyl-10,11-dihydro-3-ethoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate,

Diethyl-3,7-diethoxy-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate

Diethyl-10,11-dihydro-3-trifluoromethyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate

Diethyl-10,11-dihydro-3-methylmercapto-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate

Diethyl-10,11-dihydro-4-propylmercapto-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate

Diethyl-10,11-dihydro-3-ethylsulfonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate,and

Diethyl-3-diethylsulfamoyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5malonate.

EXAMPLE 410,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid

A solution of 0.01525 mole of diethyl10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonatein 250 ml. of methanol and 30 ml. of 5% aqueous sodium hydroxide isheated to refluxing for 2 hours. Evaporation of the solution underreduced pressure leaves an oil that is partitioned between 5% aqueoussodium hydroxide and benzene. The aqueous alkaline layer is separated,cooled in ice, and acidified with dilute hydrochloric acid. The oilyprecipitate is extracted into benzene. After concentration of the washedand dried benzene solution to a small volume, the white solid productcrystallizes and is collected; m.p. 183°-185° C. Sublimation at 115° C.and 0.05 mm. gives a purified sample, m.p. 179°-186° C.

Anal. Calc'd. for C₁₇ H₁₂ F₄ O₂ : C, 62.96; H, 3.73; F, 23.44. Found: C,63.00; H, 3.91; F, 23.31.

The procedure of the preceding paragraph is repeated using as startingmaterials, instead ofdiethyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-malonate,the products obtained in accordance with the second paragraph of Example3 with resultant production of10,11-dihydro-1,10,10,11,11-pentafluoro-5H-dibenzo[a,d]-cycloheptene-5-aceticacid,

3-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid,

10,11-dihydro-3-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid,

3,7-diethyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid,

10,11-dihydro-4-methoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid,

10,11-dihydro-3-ethoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]-cycloheptene-5-aceticacid,

3,7-diethoxy-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid,

10,11-dihydro-3-trifluoromethyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid,

10,11-dihydro-3-methylmercapto-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid,

10,11-dihydro-4-propylmercapto-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid,

10,11-dihydro-3-ethylsulfonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid, and

3-diethylsulfamoyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid.

EXAMPLE 5 10,11-Dihydro-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine

10,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-aceticacid, 0.663 g. (0.00205 mole), is dissolved in 0.4 ml. of water -- 2.5ml. of acetone. The solution is stirred, cooled in an ice-salt bath, andtreated with a solution of 0.24 g. (0.00236 mole) of triethylamine in 2ml. of acetone. A solution of 0.28 g. (0.0026 mole) of ethylchloroformate in 1.2 ml. of acetone is added dropwise and stirring iscontinued at 0° C. for 11/4 hours. A solution of 0.2 g. (0.00308 mole)of sodium azide in 0.6 ml. of water then is added dropwise. After 1 hourof stirring in the cold, the mixture is poured into 80 ml. of water andthe oily product extracted into toluene. The washed and dried tolueneextract is heated at 90° C. for 20 minutes and then evaporated todryness under reduced pressure. The residual oil is dissolved in 10 ml.of absolute methanol and after heating the solution to refluxing for 15minutes, the solvent is evaporated under reduced pressure.Recrystallization of the residual solid from hexane yields the whitecrystalline product, m.p. 137°-139.5° C.

The procedure of the preceding paragraph is repeated using as startingmaterials, instead of10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo-cycloheptene-5-aceticacid, the products obtained in accordance with the second paragraph ofExample 4 with resultant production of

10,11-dihydro-N-methoxycarbonyl-1,10,10,11,11-pentafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

3-chloro-10,11-dihydro-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-methyl-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

3,7-diethyl-10,11-dihydro-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-4-methoxy-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-ethoxy-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

3-diethoxy-10,11-dihydro-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-trifluoromethyl-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-methylmercapto-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-4-propylmercapto-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-ethylsulfonyl-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5methylamine,and

3-diethysulfamoyl-10,11-dihydro-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine.

EXAMPLE 610,11-Dihydro-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine

Lithium aluminum hydride, 0.119 g. (0.00313 mole) is weighed undernitrogen, transferred to a dry, nitrogen-flushed reaction flask, andsuspended in 5 ml. of absolute ether. A solution of 0.416 g. (0.00313mole) of anhydrous aluminum chloride in 10 ml. of absolute ether isadded dropwise. After stirring the mixture for several minutes, asolution of 0.3 g. (0.00085 mole) of10,11-dihydro-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5methylaminein 10 ml. of absolute ether is added dropwise. Stirring is continuedovernight in a nitrogen atmosphere. The mixture is cooled in an ice bathand hydrolyzed by the dropwise addition of 4 ml. of water. The etherealsolution is decanted and the gelatinous precipitate, after washing twicewith ether, is treated with 8 ml. of 40% aqueous sodium hydroxide and 40ml. of water. The oily base is extracted into benzene. Evaporation ofthe washed and dried benzene extract under reduced pressure leaves theproduct as the residual oil. The base is converted to the hydrochloridesalt by treating a solution in absolute ethanol with a slight excess ofethanolic hydrogen chloride. After dilution with absolute ether, theprecipitated hydrochloride is collected; m.p. 249.5°-251° C.Recrystallization from isopropyl alcohol-absolute ether gives a purifiedsample, m.p. 252°-253° C.

Anal. Calc'd. for C₁₇ H₁₅ F₄ N.HCl: C, 59.05; H, 4.67; N, 4.05. Found:C, 58.92; H, 4.79; N, 4.07.

The procedure of the preceding paragraph is repeated using as thestarting materials, instead of10,11-dihydro-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,the products obtained in accordance with the second paragraph of Example5 with the resultant production of

10,11-dihydro-N-methyl-1,10,10,11,11-pentafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

3-chloro-10,11-dihydro-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-methyl-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

3,7-diethyl-10,11-dihydro-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-4-methoxy-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-ethoxy-N-methyl-10,10,11,11tetrafluoro-5H-dibenzo[a,d]cyclopheptene-5methylamine,

3,7-diethoxy-10,11-dihydro-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5methylamine,

10,11-dihydro-3-trifluoromethyl-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-methylmercapto-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-4-propylmercapto-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-ethylsulfonyl-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5methylamine,and

3-diethylsulfamoyl-10,11-dihydro-N-methyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine.

EXAMPLE 710,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo-[a,d]cycloheptene-5methylamine

10,11-Dihydro-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,0.5 g. (0.001417 mole), together with 5 ml. of glacial acetic acid, 2.5ml. of water, and 2.5 ml. of concentrated hydrochloric acid, is stirredat reflux for 20 hours. Evaporation of the solution under reducedpressure and recrystallization of the residual solid from absolutemethano-absolute ether yields the hydrochloride salt of the product,m.p. 250°-255° C. Repeated crystallizations from isopropyl alcohol -absolute ether afford the analytical sample, m.p. 268°-271° C.

Anal. Calc'd. for C₁₆ H₁₃ F₄ N.HCl: C, 57.29; H, 4.25; Cl, 10.69. Found:C, 57.84; H, 4.32; Cl, 10.73.

The procedure of the preceding paragraph is repeated using as thestarting materials, instead of10,11-dihydro-N-methoxycarbonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]-cycloheptene-5-methylamine,the products obtained in accordance with the second paragraph of Example6 with the resultant production of

10,11-dihydro-1,10,10,11,11-pentafluoro-5H-dibenzo[a,d]-cycloheptene-5-methylamine,

3-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo-[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-methyl-10,10,11,11-tetrafluoro-5H-dibenzo-[a,d]cycloheptene-5methylamine,

3,7-diethyl-10,11-dihydro-10,10,11,11,-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-4-methoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-ethoxy-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

3,7-diethoxy-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-trifluoromethyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-methylmercapto-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

10,11-dihydro-3-ethysulfonyl-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,

3-ethylsulfamoyl-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,and

10,11-dihydro-4-propylmercapto-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine.

EXAMPLE 8 METHOD OF TESTING FOR ANTIARRHYTHMIC ACTIVITY -- PREVENTION ORMODIFICATION OF VENTRICULAR ARRHYTHMIA

Beagle dogs of either sex and weighing from 6 to 10 kg. are anesthetizedby the administration of vinbartital employing a dose of 50 mg. /kg. ofbody weight and the mean arterial pressure and the electrocardiogram(Lead II) are recorded. The animals are artifically respired and thethorax opened at the fourth or fifth interspace. The pericardium isopened and a portion of the anterior descending coronary artery justdistal to the origin is freed from the surrounding tissue. Mecamylamineis administered to slow the heart rate and 10 minutes later the compoundto be tested for antiarrhythmic effect is adminstered intravenously. Tenminutes after administration of the test compound 0.0035 ml. /kg. oftetrafluorohexachlorobutane (TFHCB), a sclerosing agent which producesmyocardial infarction and arrhythmia in dogs (Ascanio et al., J. Am.Physiol. 209: 1081-1099 (1965)) is injected into the coronary artery. Incontrol animals, this does of TFHCB produces a ventricular arrhythmia in100% of the animals tested and death in 33% of the animals tested as aresult of ventricular fibrillation.

Following injection of the sclerosing agent, an electrocardiogram isrecorded at two-minute intervals for one hour and the average number ofelectrical (ECG) complexes per minute and the percent normal complexescalculated. The data obtained with different doses of the test compoundsis plotted and the does estimated to protect the animals is estimatedgraphically (ED₈₀ mg./kg.). This figure indicates that 80% of all theelectrical (ECG) complexes are normal.

The compound,10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,is active as an antiarrhythmic agent.

EXAMPLE 9 METHOD OF TESTING FOR ANTIARRHYTHMIC ACTIVITY - TREATMENT OFEXISTING ARRHYTHMIA

The compounds to be tested for antiarrhythmic effect are tested inanimals with an arrhythmia due to ligation of a branch of the coronaryartery. The technique used to produce the arrhythmia is described byHarris (Circ. 1:1318-1328, 1950). The test compounds are examined fortheir effect on total electrical rate (ECG) and ventricular ectopicrhythms.

The test animals are 6 to 10 kg. unanesthetized beagle dogs in which theanterior descending coronary artery has been ligated one or two daysprior to the test. Lead II of the ECG is recorded, the total electricalrate per minute is computed and the percent normal complexes calculatedat 15-minute intervals before and after administration of the testcompound. The measurements are made over a total of two hours for the 60minutes during and the 60 minutes following administration of the testdrug. To evaluate the effectiveness of the compound, data from four ormore observations are averaged and plotted graphically. The area formedby the curves is measured with a planimeter. The degree of effectivenessof the test compounds is related to the size of the area under thecurve. The test compound is compared to the known antiarrhythmic agent,quinidine sulfate, in this test.

The compound10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylamine,is active in this test as an antiarrhythmic agent.

What is claimed is:
 1. A compound of the formula ##STR5## in which atleast one of the hydrogens at the 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-positions is replaced with a substituent selected from halogen,loweralkyl of from 1-6 carbon atoms, loweralkoxy of from 1-5 carbonatoms, trifluoromethyl, loweralkylmercapto of from 1-6 carbon atoms,loweralkylsulfonyl of from 1-6 carbon atoms and dialkylsulfamoyl of from2-8 carbon atoms. 2.10,11-Dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene-5-methylisocyanate.